WO2024007464A1 - Method for producing deuterated compound with tower device - Google Patents

Method for producing deuterated compound with tower device Download PDF

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WO2024007464A1
WO2024007464A1 PCT/CN2022/124287 CN2022124287W WO2024007464A1 WO 2024007464 A1 WO2024007464 A1 WO 2024007464A1 CN 2022124287 W CN2022124287 W CN 2022124287W WO 2024007464 A1 WO2024007464 A1 WO 2024007464A1
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tower
deuterium source
deuterium
catalyst
deuterated
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PCT/CN2022/124287
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French (fr)
Chinese (zh)
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高章华
吴涛
陈佳
江之江
唐建波
陶炜坚
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宁波萃英化学技术有限公司
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Priority to KR1020247008915A priority Critical patent/KR20240050383A/en
Publication of WO2024007464A1 publication Critical patent/WO2024007464A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

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  • the present invention relates to the technical field of producing deuterated compounds, and in particular to a method for producing deuterated compounds using tower equipment.
  • Deuterium-containing organics are becoming increasingly important as knowledge of them increases.
  • deuterated reagents such as CDCl 3 , deuterated DMSO, deuterated methanol, deuterated acetone, etc. can be used to avoid the interference of hydrogen atoms in ordinary solvents, so that the number of hydrogen atoms in organic molecules can be accurately analyzed.
  • Monodeuterated methanol and ethanol are relatively important deuterated products and are often used as deuterium sources for deuteration reactions of other substances; deuterated acetone, in addition to being used as a deuterium source, is also used as a conventional deuterated solvent for nuclear magnetic detection. kind of.
  • monodeuterated methanol, ethanol, deuterated acetone and deuterated dimethyl sulfoxide are basically prepared by the intermittent iteration method of the reactor. It often requires 10 to 20 levels of iterative reactions to achieve effective deuteration. The entire system is relatively complex. It is complicated and requires separation at each level of iteration, which is extremely inefficient.
  • the object of the present invention is to provide a method for producing deuterated compounds using tower equipment.
  • This method uses an active deuterium reagent as a deuterium source and completes the continuous improvement of the deuterium content in the product without the use of a catalyst or a suitable base as a catalyst. , and finally generate qualified deuterated products, which have the advantages of high deuterium isotope utilization, good deuteration effect, and high energy efficiency.
  • a method for producing deuterated compounds using tower equipment A rectification tower is used as a reactor. Under the protection of an inert atmosphere, organic reagent raw materials are passed through a steam generator into the rectification tower in the form of steam from the lower part of the rectification tower, and the deuterium source is Reagents or catalyst-containing deuterium source reagents enter the distillation tower from the upper part of the distillation tower after being preheated. The top-down deuterium source reagents or catalyst-containing deuterium source reagents and the bottom-up organic reagent raw material steam are in the tower. A hydrogen-deuterium exchange reaction occurs, and the product is separated at the top of the tower to obtain deuterated products;
  • the deuterium source reagent enters the rectification tower in the form of steam from the lower part of the rectification tower through the steam generator, and the organic reagent raw materials or organic reagent raw materials containing catalysts are preheated. Then it enters the distillation tower from the upper part of the distillation tower.
  • the top-down organic reagent raw materials or organic reagent raw materials containing catalysts and the bottom-up deuterium source reagent vapor undergo a hydrogen-deuterium exchange reaction in the tower, and proceed at the bottom of the tower.
  • the product is isolated to obtain the deuterated product.
  • the deuterium source reagent When the boiling point of the deuterium source reagent is higher than the organic reagent raw material, the deuterium source reagent enters as a liquid from top to bottom, and the organic reagent raw material enters as steam from bottom to top; when the boiling point of the deuterium source reagent is lower than the organic reagent raw material, then The organic reagent raw materials enter from top to bottom as liquid, and the deuterium source reagent and organic reagent raw materials enter from bottom to top as steam.
  • the present invention uses tower equipment to effectively avoid multiple separation processes in the actual process, and returns the multiple iteration processes to the gas-liquid phase interfaces in the tower.
  • the method has good operability and stability. It has the characteristics of high hydrogen-deuterium exchange efficiency, high deuterium utilization rate, and simple product separation.
  • the mass concentration of the catalyst in the catalyst-containing organic reagent raw material is 0.005-1%.
  • the temperature of the tower body of the distillation tower is generally 60-100°C, and the temperature at the top of the tower is slightly higher (1-5°C higher) than the boiling point of the deuterated product.
  • the deuterium source reagent is selected from one or two of heavy water, monodeuterated methanol, monodeuterated ethanol, deuterated acetone, deuterated acetonitrile, and deuterated dimethyl sulfoxide.
  • the deuterium source reagent is most preferably heavy water.
  • the inert atmosphere is a gas environment composed of nitrogen or argon.
  • the catalyst is selected from one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
  • the catalyst is dried before use.
  • the catalyst drying parameters are: vacuum drying at 200°C for 2 hours; after drying, it is mixed with a deuterium source reagent in an inert environment to form a solution with a required concentration.
  • the mass concentration of the catalyst in the catalyst-containing deuterium source reagent is 0.005-1%.
  • the temperature of the deuterium source reagent or the catalyst-containing deuterium source reagent after preheating is controlled to be 0 to 3°C below the boiling point of the deuterium source reagent.
  • the temperature is controlled to 98-101°C.
  • the temperature of the reboiler at the bottom of the distillation tower is 10-20°C above the boiling point of the product, the deuterium source reagent content after the isotope abundance of the bottom discharge is reduced is controlled at 85-98%, and the deuteration degree Control it at 10-60%.
  • the temperature of the reboiler at the bottom of the tower is 110-120°C, the water content discharged from the bottom of the tower is controlled at 85-98%, and the deuterated degree of the discharge water is controlled at 10-60%.
  • the discharge speed of the tower bottom reboiler is actually adjusted according to the liquid level.
  • the optional discharge speed is 1300 ⁇ 1800g/hr.
  • the feed flow rate of the deuterium source reagent or catalyst-containing deuterium source reagent is 1300-1800g/hr.
  • the organic reagent raw material is selected from one of methanol, ethanol, acetone, and DMSO.
  • the speed at which the steam generator replenishes solvent needs to be adjusted according to its liquid level, and generally needs to be synchronized with the amount of steam evaporation.
  • the acetone steam flow rate output by the steam generator is 400-500L/h.
  • the steam flow rate of methanol and ethanol output from the steam generator is 2000-3500L/h.
  • the reflux ratio of the total condenser at the top of the tower is controlled so that the moisture content of the deuterated product discharged from the top of the tower is less than 6 wt%.
  • the deuterated degree of the product discharged from the top of the tower is greater than 98%.
  • the reflux ratio of the total condenser at the top of the tower is about 0.5.
  • the beneficial effects of the present invention are: the use of tower equipment effectively avoids multiple separation processes in the actual process, and returns the multiple iteration processes to the gas-liquid phase interfaces in the tower.
  • the method has better Operability and stability, high hydrogen-deuterium exchange efficiency, high deuterium conversion rate, and simple product separation.
  • Figure 1 is a schematic structural diagram of the present invention.
  • the raw materials and equipment used can be purchased from the market or are commonly used in the field.
  • the methods in the following examples are all conventional methods in the art unless otherwise specified.
  • the production equipment of the present invention is shown in Figure 1, including a rectification tower 1, an organic reagent raw material storage tank 2 is connected to a steam generator 4 through a pipeline, and the outlet of the steam generator 4 is connected to the lower part of the rectification tower 1 through a pipeline.
  • the catalyst-containing deuterium source reagent storage tank 3 is connected to the heater 5 through a pipeline, and the outlet of the heater 5 is connected to the feed port at the upper part of the distillation tower 1 through a pipeline; there is a tower at the bottom of the distillation tower 1
  • Bottom reboiler 6 the top of the distillation tower 1 is provided with a total condenser 7 at the top of the tower, a deuterated product storage tank 8 is provided next to the total condenser at the top of the tower, and the deuterated product storage tank 8 is connected to the total condenser at the top of the tower.
  • the bottom reboiler 6 and the deuterated product storage tank 8 are equipped with a liquid level controller 9 and a temperature display 10. The liquid level controller is used to detect and control the liquid level.
  • the top-down deuterium source reagent and the bottom-down deuterium source reagent are The organic reagent raw material vapor on the tower undergoes deuteration reaction in the tower.
  • a method for producing deuterated compounds using tower equipment A rectification tower is used as a reactor. Under the protection of an inert atmosphere, organic reagent raw materials are passed through a steam generator into the rectification tower in the form of steam from the lower part of the rectification tower, and the deuterium source is Reagents or catalyst-containing deuterium source reagents enter the distillation tower from the upper part of the distillation tower after being preheated. The top-down deuterium source reagents or catalyst-containing deuterium source reagents and the bottom-up organic reagent raw material steam are in the tower. A deuteration reaction occurs and the product is separated at the top of the tower to obtain the deuterated product.
  • the deuterium source reagent is selected from one or two types of heavy water and monodeuterated methanol.
  • the inert atmosphere is a gas environment composed of nitrogen or argon.
  • the temperature of the deuterium source reagent or the catalyst-containing deuterium source reagent after preheating is controlled to be 0 to 3°C below the boiling point of the deuterium source reagent.
  • the temperature of the reboiler at the bottom of the distillation tower is 110-120°C, the water content discharged from the bottom of the tower is controlled at 85-98%, and the deuteration degree of the discharge water is controlled at 10-60%.
  • the feed flow rate of the deuterium source reagent or the catalyst-containing deuterium source reagent is 1300-1800g/hr.
  • the organic reagent raw material is selected from one of methanol, ethanol, acetone, and DMSO.
  • the reflux ratio of the total condenser at the top of the tower is controlled so that the moisture content of the deuterated product discharged from the top of the tower is less than 6%.
  • the catalyst is selected from one or more types of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
  • the mass concentration of the catalyst in the catalyst-containing deuterium source reagent is 0.05-1%.
  • the acetone steam flow rate output by the steam generator is 400-500L/h.
  • the steam flow rate of methanol and ethanol output from the steam generator is 2000-3500L/h.
  • heater 5 heats and maintains it at 98-101°C, and controls its flow rate to 1500g/hr;
  • the finished product slowly distills out from the top of the tower, and its deuteration degree and moisture are detected.
  • Its deuteration degree is controlled by controlling the feed amount of heavy water, and its moisture content is controlled by controlling the reflux ratio (each adjustment requires 2hr stable system); until the deuteration degree of the material at the top of the tower is greater than 99% and the moisture is less than 5%; then the system is judged to be stable.
  • the parameters that need to be adjusted for the entire system are as follows:
  • the synthesized monodeuterated methanol is characterized by hydrogen nuclear magnetic spectrum: 1 H NMR (399MHz, Methanol-d 1 ) ⁇ 4.80 (s, 0.01H), 3.27 (s, 3H).
  • heater 5 heats and maintains it at 98-100°C, and controls its flow rate to 1500g/hr;
  • the finished product slowly distills out from the top of the tower, and its deuteration degree and moisture are detected.
  • Its deuteration degree is controlled by controlling the feed amount of heavy water, and its moisture content is controlled by controlling the reflux ratio (each adjustment requires 2hr stable system); until the deuteration degree of the material at the top of the tower is greater than 99% and the moisture is less than 5%; then the system is judged to be stable.
  • the parameters that need to be adjusted for the entire system are as follows:
  • the hydrogen nuclear magnetic spectrum of the synthesized monodeuterated ethanol is characterized by: 1 H NMR (399MHz, Ethenol-d 1 ) ⁇ 4.35 (t, 0.01H), 3.51 (q, 2H), 1.10 (t, 3H).
  • heater 5 starts feeding and heating the deuterium source reagent containing the catalyst (catalyst-containing heavy water, catalyst potassium carbonate, content 0.01%), heater 5 is heated and maintained at 98-101°C, and its flow rate is controlled to 1500g/hr;
  • the finished product slowly distills out from the top of the tower, and its deuteration degree and moisture are detected.
  • Its deuteration degree is controlled by controlling the feed amount of heavy water, and its moisture content is controlled by controlling the reflux ratio (each adjustment requires 2hr stable system); until the deuteration degree of the material at the top of the tower is greater than 99% and the moisture is less than 5%; then the system is judged to be stable.
  • the parameters that need to be adjusted for the entire system are as follows:
  • the hydrogen nuclear magnetic spectrum of the synthesized deuterated acetone is characterized by: 1 H NMR (399MHz, Acetone-d 6 ) ⁇ 2.05 (m, 0.05H), with dioxane as the quantitative internal standard.
  • the heater 5 is heated and maintained at 98-101°C, after the steam reaches the top of the tower Start feeding and control the flow rate to 1560g/hr;
  • the finished product slowly distills out from the top of the tower, and its deuteration degree and moisture are detected.
  • Its deuteration degree is controlled by controlling the feed amount of heavy water, and its moisture content is controlled by controlling the reflux ratio (each adjustment requires 2hr stable system); until the deuteration degree of the material at the top of the tower is greater than 99% and the moisture is less than 5%; then the system is judged to be stable.
  • the parameters that need to be adjusted for the entire system are as follows:
  • the synthesized deuterated dimethyl sulfoxide is characterized by hydrogen nuclear magnetic spectrum: 1 H NMR (399MHz, DMSO-d 6 ) ⁇ 2.50 (m, 0.05H), with dioxane as the quantitative internal standard.

Abstract

Disclosed is a method for producing a deuterated compound with a tower device. By means of using an active deuterium reagent as a deuterium source, the content of deuterium in the product is continuously improved in the absence of a catalyst or a proper alkali as a catalyst, and finally, the qualified deuterated product is generated and has the advantages of high utilization degree of deuterium isotopes, good deuteration effect, and high energy efficiency.

Description

一种利用塔设备生产氘代化合物的方法A method for producing deuterated compounds using tower equipment 技术领域Technical field
本发明涉及氘代化合物生产技术领域，特别涉及一种利用塔设备生产氘代化合物的方法。The present invention relates to the technical field of producing deuterated compounds, and in particular to a method for producing deuterated compounds using tower equipment.
背景技术Background technique
随着对含氘有机物认识的增加，含氘有机物变得越来越重要。在核磁检测中，氘代试剂如CDCl 3，氘代DMSO，氘代甲醇，氘代丙酮等可以用于避免普通溶剂的氢原子的干扰，从而可以准确地分析出有机分子的氢原子的数量，化学环境，空间关系等结构信息；由于氘的质量相对较大，碳氘键比碳氢键更为稳定，所以在药物以及功能材料等方面的氘代研究逐渐发展起来。 Deuterium-containing organics are becoming increasingly important as knowledge of them increases. In nuclear magnetic detection, deuterated reagents such as CDCl 3 , deuterated DMSO, deuterated methanol, deuterated acetone, etc. can be used to avoid the interference of hydrogen atoms in ordinary solvents, so that the number of hydrogen atoms in organic molecules can be accurately analyzed. Chemical environment, spatial relationship and other structural information; due to the relatively large mass of deuterium, carbon-deuterium bonds are more stable than carbon-hydrogen bonds, so deuterium generation research in drugs and functional materials has gradually developed.
单氘代甲醇、乙醇是一种相对重要的氘代产品，经常作为氘源对其他物质进行氘代反应；而氘代丙酮除了可以作为氘源之外，更是作为核磁检测的常规氘代溶剂的一种。Monodeuterated methanol and ethanol are relatively important deuterated products and are often used as deuterium sources for deuteration reactions of other substances; deuterated acetone, in addition to being used as a deuterium source, is also used as a conventional deuterated solvent for nuclear magnetic detection. kind of.
目前单氘代的甲醇、乙醇、氘代丙酮及氘代二甲基亚砜，基本采用反应釜间歇式迭代的方法进行制备，常需要10～20级迭代反应才能实现有效氘代，整个***较为繁杂，且每级迭代都需要分离，效率极其低下。At present, monodeuterated methanol, ethanol, deuterated acetone and deuterated dimethyl sulfoxide are basically prepared by the intermittent iteration method of the reactor. It often requires 10 to 20 levels of iterative reactions to achieve effective deuteration. The entire system is relatively complex. It is complicated and requires separation at each level of iteration, which is extremely inefficient.
发明内容Contents of the invention
本发明的目的在于提供一种利用塔设备生产氘代化合物的方法，该方法以活泼性氘试剂为氘源，在没有催化剂或合适的碱作为催化剂的基础上，完成产物中氘含量的连续提升，最终生成合格的氘代产物，具有氘同位素利用度高、氘代效果好、能效高的优点。The object of the present invention is to provide a method for producing deuterated compounds using tower equipment. This method uses an active deuterium reagent as a deuterium source and completes the continuous improvement of the deuterium content in the product without the use of a catalyst or a suitable base as a catalyst. , and finally generate qualified deuterated products, which have the advantages of high deuterium isotope utilization, good deuteration effect, and high energy efficiency.
本发明解决其技术问题所采用的技术方案是：The technical solutions adopted by the present invention to solve the technical problems are:
一种利用塔设备生产氘代化合物的方法，以精馏塔作为反应器，在惰性气氛保护下，将有机试剂原料经蒸汽发生器以蒸汽形式从精馏塔下部进入精馏塔，将氘源试剂或含催化剂的氘源试剂经预热后从精馏塔上部进入精馏塔，自上而下的氘源试剂或含催化剂的氘源试剂与自下而上的有机试剂原料蒸汽在塔内发生氢氘交换反应，并在塔顶进行产物分离，从而获得氘代产物；A method for producing deuterated compounds using tower equipment. A rectification tower is used as a reactor. Under the protection of an inert atmosphere, organic reagent raw materials are passed through a steam generator into the rectification tower in the form of steam from the lower part of the rectification tower, and the deuterium source is Reagents or catalyst-containing deuterium source reagents enter the distillation tower from the upper part of the distillation tower after being preheated. The top-down deuterium source reagents or catalyst-containing deuterium source reagents and the bottom-up organic reagent raw material steam are in the tower. A hydrogen-deuterium exchange reaction occurs, and the product is separated at the top of the tower to obtain deuterated products;
或以精馏塔作为反应器，在惰性气氛保护下，将氘源试剂经蒸汽发生器以蒸汽形式从精馏塔下部进入精馏塔，将有机试剂原料或含催化剂的有机试剂原料经预热后从精馏塔上部进入精馏塔，自上而下的有机试剂原料或含催化剂的有机试剂原料与自下而上的氘源试剂蒸汽在塔内发生氢氘交换反应，并在塔底进行产物分离，从而获得氘代产物。Or use the rectification tower as the reactor, and under the protection of an inert atmosphere, the deuterium source reagent enters the rectification tower in the form of steam from the lower part of the rectification tower through the steam generator, and the organic reagent raw materials or organic reagent raw materials containing catalysts are preheated. Then it enters the distillation tower from the upper part of the distillation tower. The top-down organic reagent raw materials or organic reagent raw materials containing catalysts and the bottom-up deuterium source reagent vapor undergo a hydrogen-deuterium exchange reaction in the tower, and proceed at the bottom of the tower. The product is isolated to obtain the deuterated product.
当氘源试剂的沸点高于有机试剂原料时，则氘源试剂自上而下以液体进入，有机试剂 原料自下而上以蒸汽进入；当氘源试剂的沸点低于有机试剂原料时，则有机试剂原料自上而下以液体进入，氘源试剂有机试剂原料自下而上以蒸汽进入。When the boiling point of the deuterium source reagent is higher than the organic reagent raw material, the deuterium source reagent enters as a liquid from top to bottom, and the organic reagent raw material enters as steam from bottom to top; when the boiling point of the deuterium source reagent is lower than the organic reagent raw material, then The organic reagent raw materials enter from top to bottom as liquid, and the deuterium source reagent and organic reagent raw materials enter from bottom to top as steam.
本发明利用塔式设备使得实际工艺中有效的规避了多次分离的过程，且把多次迭代的工艺回归至塔内各气液相界面上进行，其方法具有较好的可操作性和稳定性，氢氘交换效率高、氘利用率高、产物分离简易等特点。The present invention uses tower equipment to effectively avoid multiple separation processes in the actual process, and returns the multiple iteration processes to the gas-liquid phase interfaces in the tower. The method has good operability and stability. It has the characteristics of high hydrogen-deuterium exchange efficiency, high deuterium utilization rate, and simple product separation.
含催化剂的有机试剂原料中催化剂的质量浓度为0.005-1％。The mass concentration of the catalyst in the catalyst-containing organic reagent raw material is 0.005-1%.
精馏塔的塔身温度一般为60-100℃，塔顶的温度略高于(高1-5℃)氘代产品沸点。The temperature of the tower body of the distillation tower is generally 60-100°C, and the temperature at the top of the tower is slightly higher (1-5°C higher) than the boiling point of the deuterated product.
作为优选，所述氘源试剂选自重水、单氘代甲醇、单氘代乙醇、氘代丙酮、氘代乙腈、氘代二甲基亚砜中一种或两种。氘源试剂最优选为重水。Preferably, the deuterium source reagent is selected from one or two of heavy water, monodeuterated methanol, monodeuterated ethanol, deuterated acetone, deuterated acetonitrile, and deuterated dimethyl sulfoxide. The deuterium source reagent is most preferably heavy water.
作为优选，所述惰性气氛为由氮气或氩气所构成的气体环境。Preferably, the inert atmosphere is a gas environment composed of nitrogen or argon.
作为优选，所述催化剂选自氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种或多种。所述催化剂先干燥后再使用，催化剂干燥的参数为：200℃下真空干燥2hr；干燥后在惰性环境中与氘源试剂配置成要求浓度的溶液。Preferably, the catalyst is selected from one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate. The catalyst is dried before use. The catalyst drying parameters are: vacuum drying at 200°C for 2 hours; after drying, it is mixed with a deuterium source reagent in an inert environment to form a solution with a required concentration.
作为优选，含催化剂的氘源试剂中催化剂的质量浓度为0.005-1％。Preferably, the mass concentration of the catalyst in the catalyst-containing deuterium source reagent is 0.005-1%.
作为优选，氘源试剂或含催化剂的氘源试剂经预热后的温度控制为在氘源试剂的沸点以下0～3℃。比如，重水做氘源试剂时，温度控制为98-101℃。Preferably, the temperature of the deuterium source reagent or the catalyst-containing deuterium source reagent after preheating is controlled to be 0 to 3°C below the boiling point of the deuterium source reagent. For example, when heavy water is used as a deuterium source reagent, the temperature is controlled to 98-101°C.
作为优选，所述精馏塔的塔底再沸器的温度为产物沸点以上10-20℃，塔底出料的同位素丰度下降后的氘源试剂含量控制在85-98％，氘代度控制在10-60％。比如，重水做氘源试剂时，塔底再沸器的温度为110-120℃，塔底出料的水含量控制在85-98％，出料水氘代度控制在10～60％。塔底再沸器的出料速度实际根据液位高低进行调整，可选的一种出料速度为1300～1800g/hr。Preferably, the temperature of the reboiler at the bottom of the distillation tower is 10-20°C above the boiling point of the product, the deuterium source reagent content after the isotope abundance of the bottom discharge is reduced is controlled at 85-98%, and the deuteration degree Control it at 10-60%. For example, when heavy water is used as the deuterium source reagent, the temperature of the reboiler at the bottom of the tower is 110-120°C, the water content discharged from the bottom of the tower is controlled at 85-98%, and the deuterated degree of the discharge water is controlled at 10-60%. The discharge speed of the tower bottom reboiler is actually adjusted according to the liquid level. The optional discharge speed is 1300~1800g/hr.
作为优选，氘源试剂或含催化剂的氘源试剂的进料流量为1300-1800g/hr。Preferably, the feed flow rate of the deuterium source reagent or catalyst-containing deuterium source reagent is 1300-1800g/hr.
作为优选，所述有机试剂原料选自甲醇、乙醇、丙酮、DMSO中的一种。蒸汽发生器补充溶剂的速度需要根据其液位进行调整，一般需要跟蒸汽蒸发量同步。蒸汽发生器输出的丙酮蒸汽流量为400-500L/h。蒸汽发生器输出的甲醇和乙醇的蒸汽流量为2000-3500L/h。Preferably, the organic reagent raw material is selected from one of methanol, ethanol, acetone, and DMSO. The speed at which the steam generator replenishes solvent needs to be adjusted according to its liquid level, and generally needs to be synchronized with the amount of steam evaporation. The acetone steam flow rate output by the steam generator is 400-500L/h. The steam flow rate of methanol and ethanol output from the steam generator is 2000-3500L/h.
作为优选，控制塔顶全凝器的回流比，使得塔顶出料的氘代产物的含水量低于6wt％。塔顶出料的产物氘代度大于98％。塔顶全凝器的回流比为0.5左右。Preferably, the reflux ratio of the total condenser at the top of the tower is controlled so that the moisture content of the deuterated product discharged from the top of the tower is less than 6 wt%. The deuterated degree of the product discharged from the top of the tower is greater than 98%. The reflux ratio of the total condenser at the top of the tower is about 0.5.
本发明的有益效果是：利用塔式设备使得实际工艺中有效的规避了多次分离的过程，且把多次迭代的工艺回归至塔内各气液相界面上进行，其方法具有较好的可操作性和稳定性，氢氘交换效率高、氘转化率高、产物分离简易等特点。The beneficial effects of the present invention are: the use of tower equipment effectively avoids multiple separation processes in the actual process, and returns the multiple iteration processes to the gas-liquid phase interfaces in the tower. The method has better Operability and stability, high hydrogen-deuterium exchange efficiency, high deuterium conversion rate, and simple product separation.
附图说明Description of the drawings
图1是本发明的一种结构示意图。Figure 1 is a schematic structural diagram of the present invention.
具体实施方式Detailed ways
下面通过具体实施例，对本发明的技术方案作进一步的具体说明。The technical solution of the present invention will be further described in detail below through specific examples.
本发明中，若非特指，所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法，如无特别说明，均为本领域的常规方法。In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the field. The methods in the following examples are all conventional methods in the art unless otherwise specified.
本发明的生产设备如图1所示，包括精馏塔1，有机试剂原料储罐2通过管路连接至蒸汽发生器4，蒸汽发生器4的出口通过管路连接至精馏塔1下部的进料口；含催化剂的氘源试剂储罐3通过管路连接至加热器5，加热器5的出口通过管路连接至精馏塔1上部的进料口；精馏塔1底部设有塔底再沸器6，精馏塔1顶部设有塔顶全凝器7，塔顶全凝器旁设置氘代产物储罐8，氘代产物储罐8与塔顶全凝器连接。塔底再沸器6和氘代产物储罐8上均装有液位控制器9和温度显示器10，液位控制器用于检测并控制液位，自上而下的氘源试剂与自下而上的有机试剂原料蒸汽在塔内发生氘代反应。The production equipment of the present invention is shown in Figure 1, including a rectification tower 1, an organic reagent raw material storage tank 2 is connected to a steam generator 4 through a pipeline, and the outlet of the steam generator 4 is connected to the lower part of the rectification tower 1 through a pipeline. Feed port; the catalyst-containing deuterium source reagent storage tank 3 is connected to the heater 5 through a pipeline, and the outlet of the heater 5 is connected to the feed port at the upper part of the distillation tower 1 through a pipeline; there is a tower at the bottom of the distillation tower 1 Bottom reboiler 6, the top of the distillation tower 1 is provided with a total condenser 7 at the top of the tower, a deuterated product storage tank 8 is provided next to the total condenser at the top of the tower, and the deuterated product storage tank 8 is connected to the total condenser at the top of the tower. The bottom reboiler 6 and the deuterated product storage tank 8 are equipped with a liquid level controller 9 and a temperature display 10. The liquid level controller is used to detect and control the liquid level. The top-down deuterium source reagent and the bottom-down deuterium source reagent are The organic reagent raw material vapor on the tower undergoes deuteration reaction in the tower.
部分氘代反应视图：Partial deuteration reaction view:
CH 3OH+D 2O→CH 3OD CH 3 OH+D 2 O→CH 3 OD
Figure PCTCN2022124287-appb-000001
Figure PCTCN2022124287-appb-000001
总实施方案：Overall implementation plan:
一种利用塔设备生产氘代化合物的方法，以精馏塔作为反应器，在惰性气氛保护下，将有机试剂原料经蒸汽发生器以蒸汽形式从精馏塔下部进入精馏塔，将氘源试剂或含催化剂的氘源试剂经预热后从精馏塔上部进入精馏塔，自上而下的氘源试剂或含催化剂的氘源试剂与自下而上的有机试剂原料蒸汽在塔内发生氘代反应，并在塔顶进行产物分离，从而获得氘代产物。A method for producing deuterated compounds using tower equipment. A rectification tower is used as a reactor. Under the protection of an inert atmosphere, organic reagent raw materials are passed through a steam generator into the rectification tower in the form of steam from the lower part of the rectification tower, and the deuterium source is Reagents or catalyst-containing deuterium source reagents enter the distillation tower from the upper part of the distillation tower after being preheated. The top-down deuterium source reagents or catalyst-containing deuterium source reagents and the bottom-up organic reagent raw material steam are in the tower. A deuteration reaction occurs and the product is separated at the top of the tower to obtain the deuterated product.
所述氘源试剂选自重水、单氘代甲醇中一种或两种。所述惰性气氛为由氮气或氩气所构成的气体环境。氘源试剂或含催化剂的氘源试剂经预热后的温度控制为在氘源试剂的沸点以下0～3℃。所述精馏塔的塔底再沸器的温度为110-120℃，塔底出料的水含量控制在85-98％；出料水氘代度控制在10-60％。氘源试剂或含催化剂的氘源试剂的进料流量为1300-1800g/hr。所述有机试剂原料选自甲醇、乙醇、丙酮、DMSO中的一种。控制塔顶全凝器的回流比，使得塔顶出料的氘代产物的含水量低于6％。The deuterium source reagent is selected from one or two types of heavy water and monodeuterated methanol. The inert atmosphere is a gas environment composed of nitrogen or argon. The temperature of the deuterium source reagent or the catalyst-containing deuterium source reagent after preheating is controlled to be 0 to 3°C below the boiling point of the deuterium source reagent. The temperature of the reboiler at the bottom of the distillation tower is 110-120°C, the water content discharged from the bottom of the tower is controlled at 85-98%, and the deuteration degree of the discharge water is controlled at 10-60%. The feed flow rate of the deuterium source reagent or the catalyst-containing deuterium source reagent is 1300-1800g/hr. The organic reagent raw material is selected from one of methanol, ethanol, acetone, and DMSO. The reflux ratio of the total condenser at the top of the tower is controlled so that the moisture content of the deuterated product discharged from the top of the tower is less than 6%.
所述催化剂选自氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种或多种。含催化剂的氘源试剂中催化剂的质量浓度为0.05-1％。蒸汽发生器输出的丙酮蒸汽流量为400-500L/h。蒸汽发生器输出的甲醇和乙醇的蒸汽流量为2000-3500L/h。The catalyst is selected from one or more types of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate. The mass concentration of the catalyst in the catalyst-containing deuterium source reagent is 0.05-1%. The acetone steam flow rate output by the steam generator is 400-500L/h. The steam flow rate of methanol and ethanol output from the steam generator is 2000-3500L/h.
实施例1单氘代甲醇的合成：Example 1 Synthesis of monodeuterated methanol:
于蒸汽发生器4中加入100kg的甲醇，加热升温，控制其蒸汽流量大约3100L/hr(约4000g/hr)，开启溶剂补充泵，维持甲醇溶剂的液位基本保持不变；Add 100kg of methanol to the steam generator 4, heat it up, control the steam flow to approximately 3100L/hr (approximately 4000g/hr), start the solvent replenishing pump, and keep the liquid level of the methanol solvent basically unchanged;
开启重水加料及加热，加热器5加热并维持在98-101℃，控制其流量为1500g/hr；Start heavy water feeding and heating, heater 5 heats and maintains it at 98-101°C, and controls its flow rate to 1500g/hr;
***运行1hr后，开启塔底再沸器6，控制温度110℃；After the system runs for 1 hour, open the bottom reboiler 6 and control the temperature to 110°C;
随着时间的推进，塔顶慢慢有成品馏出，检测其氘代度及水分，通过控制重水进料量来控制其氘代度，通过控制回流比来控制其水分含量(每次调整需要2hr稳定***)；直到塔顶出口物料氘代度大于99％，水分小于5％；则判定***稳定，整个***需要调整的参数如下：As time goes by, the finished product slowly distills out from the top of the tower, and its deuteration degree and moisture are detected. Its deuteration degree is controlled by controlling the feed amount of heavy water, and its moisture content is controlled by controlling the reflux ratio (each adjustment requires 2hr stable system); until the deuteration degree of the material at the top of the tower is greater than 99% and the moisture is less than 5%; then the system is judged to be stable. The parameters that need to be adjusted for the entire system are as follows:
1、重水进料流量，用于调节产品氘代度；1. Heavy water feed flow, used to adjust the deuteration degree of the product;
2、回流比，用于调节水分含量；2. Reflux ratio, used to adjust moisture content;
3、再沸器温度，用于综合调节。3. Reboiler temperature, used for comprehensive adjustment.
合成的单氘代甲醇，其核磁氢谱表征为： 1H NMR(399MHz,Methanol-d 1)δ4.80(s,0.01H),3.27(s,3H)。 The synthesized monodeuterated methanol is characterized by hydrogen nuclear magnetic spectrum: 1 H NMR (399MHz, Methanol-d 1 ) δ4.80 (s, 0.01H), 3.27 (s, 3H).
实施例2单氘代乙醇的合成Example 2 Synthesis of monodeuterated ethanol
于蒸汽发生器4中加入100kg的乙醇，加热升温，控制其蒸汽流量大约3180L/hr(约5520g/hr)，开启溶剂补充泵，维持溶剂的液位基本保持不变；Add 100kg of ethanol to the steam generator 4, heat it up, control the steam flow to about 3180L/hr (about 5520g/hr), start the solvent replenishing pump, and keep the solvent level basically unchanged;
开启重水加料及加热，加热器5加热并维持在98-100℃，控制其流量为1500g/hr；Start heavy water feeding and heating, heater 5 heats and maintains it at 98-100°C, and controls its flow rate to 1500g/hr;
***运行1hr后，开启塔底再沸器6，控制温度110℃；After the system runs for 1 hour, open the bottom reboiler 6 and control the temperature to 110°C;
随着时间的推进，塔顶慢慢有成品馏出，检测其氘代度及水分，通过控制重水进料量来控制其氘代度，通过控制回流比来控制其水分含量(每次调整需要2hr稳定***)；直到塔顶出口物料氘代度大于99％，水分小于5％；则判定***稳定，整个***需要调整的参数如下：As time goes by, the finished product slowly distills out from the top of the tower, and its deuteration degree and moisture are detected. Its deuteration degree is controlled by controlling the feed amount of heavy water, and its moisture content is controlled by controlling the reflux ratio (each adjustment requires 2hr stable system); until the deuteration degree of the material at the top of the tower is greater than 99% and the moisture is less than 5%; then the system is judged to be stable. The parameters that need to be adjusted for the entire system are as follows:
1、重水进料流量，用于调节产品氘代度；1. Heavy water feed flow, used to adjust the deuteration degree of the product;
2、回流比，用于调节水分含量；2. Reflux ratio, used to adjust moisture content;
3、再沸器温度，用于综合调节。3. Reboiler temperature, used for comprehensive adjustment.
合成的单氘代乙醇，其核磁氢谱表征为： 1H NMR(399MHz,Ethenol-d 1)δ4.35(t,0.01H),3.51(q,2H),1.10(t,3H)。 The hydrogen nuclear magnetic spectrum of the synthesized monodeuterated ethanol is characterized by: 1 H NMR (399MHz, Ethenol-d 1 ) δ4.35 (t, 0.01H), 3.51 (q, 2H), 1.10 (t, 3H).
实施例3氘代丙酮的合成：Example 3 Synthesis of deuterated acetone:
于蒸汽发生器4中加入100kg的丙酮，加热升温，控制其蒸汽流量大约450L/hr(约1160g/hr)，开启溶剂补充泵，维持溶剂的液位基本保持不变；Add 100kg of acetone to the steam generator 4, heat it up, control the steam flow to about 450L/hr (about 1160g/hr), start the solvent replenishing pump, and keep the solvent level basically unchanged;
开启含催化剂的氘源试剂加料及加热(含催化剂的重水，催化剂碳酸钾，含量0.01％)，加热器5加热并维持在98-101℃，控制其流量为1500g/hr；Start feeding and heating the deuterium source reagent containing the catalyst (catalyst-containing heavy water, catalyst potassium carbonate, content 0.01%), heater 5 is heated and maintained at 98-101°C, and its flow rate is controlled to 1500g/hr;
***运行1hr后，开启塔底再沸器6，控制温度110℃；After the system runs for 1 hour, open the bottom reboiler 6 and control the temperature to 110°C;
随着时间的推进，塔顶慢慢有成品馏出，检测其氘代度及水分，通过控制重水进料量来控制其氘代度，通过控制回流比来控制其水分含量(每次调整需要2hr稳定***)；直到塔顶出口物料氘代度大于99％，水分小于5％；则判定***稳定，整个***需要调整的参数如下：As time goes by, the finished product slowly distills out from the top of the tower, and its deuteration degree and moisture are detected. Its deuteration degree is controlled by controlling the feed amount of heavy water, and its moisture content is controlled by controlling the reflux ratio (each adjustment requires 2hr stable system); until the deuteration degree of the material at the top of the tower is greater than 99% and the moisture is less than 5%; then the system is judged to be stable. The parameters that need to be adjusted for the entire system are as follows:
1、重水进料流量，用于调节产品氘代度；1. Heavy water feed flow, used to adjust the deuteration degree of the product;
2、回流比，用于调节水分含量；2. Reflux ratio, used to adjust moisture content;
3、再沸器温度，用于综合调节。3. Reboiler temperature, used for comprehensive adjustment.
合成的氘代丙酮，其核磁氢谱表征为： 1H NMR(399MHz,Acetone-d 6)δ2.05(m,0.05H)，以二氧六环作为定量内标。 The hydrogen nuclear magnetic spectrum of the synthesized deuterated acetone is characterized by: 1 H NMR (399MHz, Acetone-d 6 ) δ2.05 (m, 0.05H), with dioxane as the quantitative internal standard.
实施例4氘代二甲基亚砜的合成：Example 4 Synthesis of deuterated dimethyl sulfoxide:
于蒸汽发生器4中加入100kg的重水(氘代度99.9％)，加热升温，控制其蒸汽流量大约2100L/hr(约1500g/hr)，开启溶剂补充泵，维持重水的液位基本保持不变；开启塔底再沸器6，控制温度120℃；Add 100kg of heavy water (deuterated degree 99.9%) into steam generator 4, heat it up, control its steam flow to about 2100L/hr (about 1500g/hr), start the solvent replenishing pump, and keep the liquid level of the heavy water basically unchanged. ; Turn on the tower bottom reboiler 6 and control the temperature to 120°C;
开启含催化剂的有机试剂预热(含催化剂的二甲基亚砜，催化剂为50％氢氧化钠水溶液，含量1％)，加热器5加热并维持在98-101℃，在蒸汽到达塔顶后开始加料，控制其流量为1560g/hr；Start the preheating of the organic reagent containing the catalyst (dimethyl sulfoxide containing the catalyst, the catalyst is 50% sodium hydroxide aqueous solution, content 1%), the heater 5 is heated and maintained at 98-101°C, after the steam reaches the top of the tower Start feeding and control the flow rate to 1560g/hr;
随着时间的推进，塔顶慢慢有成品馏出，检测其氘代度及水分，通过控制重水进料量来控制其氘代度，通过控制回流比来控制其水分含量(每次调整需要2hr稳定***)；直到塔顶出口物料氘代度大于99％，水分小于5％；则判定***稳定，整个***需要调整的参数如下：As time goes by, the finished product slowly distills out from the top of the tower, and its deuteration degree and moisture are detected. Its deuteration degree is controlled by controlling the feed amount of heavy water, and its moisture content is controlled by controlling the reflux ratio (each adjustment requires 2hr stable system); until the deuteration degree of the material at the top of the tower is greater than 99% and the moisture is less than 5%; then the system is judged to be stable. The parameters that need to be adjusted for the entire system are as follows:
1、重水进料流量，用于调节产品氘代度；1. Heavy water feed flow, used to adjust the deuteration degree of the product;
2、回流比，用于调节水分含量；2. Reflux ratio, used to adjust moisture content;
3、再沸器温度，用于综合调节。3. Reboiler temperature, used for comprehensive adjustment.
合成的氘代二甲基亚砜，其核磁氢谱表征为： 1H NMR(399MHz,DMSO-d 6)δ2.50(m,0.05H)，以二氧六环作为定量内标。 The synthesized deuterated dimethyl sulfoxide is characterized by hydrogen nuclear magnetic spectrum: 1 H NMR (399MHz, DMSO-d 6 ) δ2.50 (m, 0.05H), with dioxane as the quantitative internal standard.
用重水为氘源，制备氘代二甲基亚砜，因为氘源试剂沸点低于产物，重水从塔底以蒸汽进料，塔顶进二甲基亚砜，最后在塔底收集DMSO-d6。Use heavy water as the deuterium source to prepare deuterated dimethyl sulfoxide. Because the boiling point of the deuterium source reagent is lower than the product, heavy water is fed as steam from the bottom of the tower, dimethyl sulfoxide is fed from the top of the tower, and finally DMSO-d6 is collected at the bottom of the tower. .
以上所述的实施例只是本发明的一种较佳的方案，并非对本发明作任何形式上的限制，在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。The above-described embodiment is only a preferred solution of the present invention and does not limit the present invention in any form. There are other variations and modifications without exceeding the technical solution described in the claims.

Claims (10)

  1. 一种利用塔设备生产氘代化合物的方法，其特征在于，以精馏塔作为反应器，在惰性气氛保护下，将有机试剂原料经蒸汽发生器以蒸汽形式从精馏塔下部进入精馏塔，将氘源试剂或含催化剂的氘源试剂经预热后从精馏塔上部进入精馏塔，自上而下的氘源试剂或含催化剂的氘源试剂与自下而上的有机试剂原料蒸汽在塔内发生氢氘交换反应，并在塔顶进行产物分离，从而获得氘代产物；A method for producing deuterated compounds using tower equipment, which is characterized in that a rectification tower is used as a reactor, and under the protection of an inert atmosphere, organic reagent raw materials are passed into the rectification tower in the form of steam from the lower part of the rectification tower through a steam generator. , preheat the deuterium source reagent or the deuterium source reagent containing the catalyst and enter the distillation tower from the upper part of the distillation tower. The top-down deuterium source reagent or the deuterium source reagent containing the catalyst and the bottom-up organic reagent raw material The steam undergoes a hydrogen-deuterium exchange reaction in the tower, and the product is separated at the top of the tower to obtain deuterated products;
    或以精馏塔作为反应器，在惰性气氛保护下，将氘源试剂经蒸汽发生器以蒸汽形式从精馏塔下部进入精馏塔，将有机试剂原料或含催化剂的有机试剂原料经预热后从精馏塔上部进入精馏塔，自上而下的有机试剂原料或含催化剂的有机试剂原料与自下而上的氘源试剂蒸汽在塔内发生氢氘交换反应，并在塔底进行产物分离，从而获得氘代产物。Or use the rectification tower as the reactor, and under the protection of an inert atmosphere, the deuterium source reagent enters the rectification tower in the form of steam from the lower part of the rectification tower through the steam generator, and the organic reagent raw materials or organic reagent raw materials containing catalysts are preheated. Then it enters the distillation tower from the upper part of the distillation tower. The top-down organic reagent raw materials or organic reagent raw materials containing catalysts and the bottom-up deuterium source reagent vapor undergo a hydrogen-deuterium exchange reaction in the tower, and proceed at the bottom of the tower. The product is isolated to obtain the deuterated product.
  2. 根据权利要求1所述的方法，其特征在于，所述氘源试剂选自重水、单氘代甲醇、单氘代乙醇、氘代丙酮、氘代乙腈、氘代二甲基亚砜中一种或两种。The method according to claim 1, wherein the deuterium source reagent is selected from one of heavy water, monodeuterated methanol, monodeuterated ethanol, deuterated acetone, deuterated acetonitrile, and deuterated dimethyl sulfoxide. Or both.
  3. 根据权利要求1所述的方法，其特征在于，所述惰性气氛为由氮气或氩气所构成的气体环境。The method of claim 1, wherein the inert atmosphere is a gas environment composed of nitrogen or argon.
  4. 根据权利要求1所述的方法，其特征在于，所述催化剂选自氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种或多种。The method according to claim 1, wherein the catalyst is selected from one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
  5. 根据权利要求1所述的方法，其特征在于，含催化剂的氘源试剂中催化剂的质量浓度为0.005-1％。The method according to claim 1, characterized in that the mass concentration of the catalyst in the deuterium source reagent containing the catalyst is 0.005-1%.
  6. 根据权利要求1所述的方法，其特征在于，氘源试剂或含催化剂的氘源试剂经预热后的温度控制为在氘源试剂的沸点以下0～3℃。The method according to claim 1, wherein the temperature of the deuterium source reagent or the catalyst-containing deuterium source reagent after preheating is controlled to be 0 to 3°C below the boiling point of the deuterium source reagent.
  7. 根据权利要求1所述的方法，其特征在于，所述精馏塔的塔底再沸器的温度为产物沸点以上10-20℃，塔底出料的同位素丰度下降后的氘源试剂含量控制在85-98％，氘代度控制在10-60％。The method according to claim 1, characterized in that the temperature of the reboiler at the bottom of the distillation tower is 10-20°C above the boiling point of the product, and the deuterium source reagent content of the bottom discharge is reduced after the isotope abundance is reduced. Control at 85-98%, and deuteration degree at 10-60%.
  8. 根据权利要求1所述的方法，其特征在于，氘源试剂或含催化剂的氘源试剂的进料流量为1300-1800g/hr。The method according to claim 1, characterized in that the feed flow rate of the deuterium source reagent or the catalyst-containing deuterium source reagent is 1300-1800g/hr.
  9. 根据权利要求1所述的方法，其特征在于，所述有机试剂原料选自甲醇、乙醇、丙酮、DMSO中的一种。The method according to claim 1, characterized in that the organic reagent raw material is selected from one of methanol, ethanol, acetone, and DMSO.
  10. 根据权利要求1所述的方法，其特征在于，控制塔顶全凝器的回流比，使得塔顶出料的氘代产物的含水量低于6wt％。The method according to claim 1, characterized in that the reflux ratio of the total condenser at the top of the tower is controlled so that the moisture content of the deuterated product discharged from the top of the tower is lower than 6wt%.
PCT/CN2022/124287 2022-07-05 2022-10-10 Method for producing deuterated compound with tower device WO2024007464A1 (en)

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